Kinetics of bromine-magnesium exchange reactions in heteroaryl bromides

Article abstract of DOI:10.1021/ol9013393

Competition experiments are reported which compare the relative reactivities of bromoheteroarenes toward i-PrMgCl.LiCl in THF at 0 °C

Full text of DOI:10.1021/ol9013393

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3502-3505
Kinetics of Bromine-Magnesium
Exchange Reactions in Heteroaryl
Bromides
Lei Shi, Yuanyuan Chu, Paul Knochel, and Herbert Mayr*
Department Chemie und Biochemie der Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstrasse 5-13 (Haus F), 81377 Mu¨nchen, Germany
herbert.mayr@cup.lmu.de
Received June 15, 2009
ABSTRACT
Competition experiments are reported which compare the relative reactivities of bromoheteroarenes toward i-PrMgCl·LiCl in THF at 0 °C.
Bromine-magnesium exchange reactions of heteroaryl bro-
mides provide an efficient entry to a wide variety of five-
and six-membered functionalized heteroaryl Grignard re-
agents, which can be used for the selective synthesis of
polyfunctionalized heterocyclic compounds, such as thiazole,
thiophene, furan, pyrrole, and pyridine derivatives.1,2 The
resulting heteroarenes are ubiquitous in natural products3 and
physiologically active compounds.4 It has been shown that
the mixed magnesium-lithium complex i-PrMgCl·LiCl has
a significantly increased reactivity in bromine-magnesium
exchange reactions compared to i-PrMgCl or i-Pr2Mg.5 In
extension of our recent investigations on the kinetics of
bromine-magnesium exchange reactions in substituted bro-
mobenzenes,6 we have now studied bromine-magnesium
exchange reactions of heteroaryl bromides in order to assist
the targeted use of these reactions for the synthesis of
polyfunctional heterocyclic compounds.
The relative exchange rates were determined by treating
mixtures of bromoheteroarenes and bromobenzenes or of two
(4) (a) Newkome, G. R.; Paudler, W. W. Contemporary Heterocyclic
Chemistry; Wiley: New York, 1982. (b) Gilchrist, T. L. Heterocyclic
Chemistry, 2nd ed.; Longman: Essex, UK, 1992. (c) Li, J. J.; Johnson, D. S.;
Sliskovic, D. R.; Roth, B. D. Contemporary Drug Synthesis; Wiley:
Hoboken, NJ, 2004. (d) Eicher, T.; Hauptmann, S. The Chemistry of
Heterocycles: Structures, Reactions, Synthesis, and Applications, 2nd ed.;
Wiley-VCH: Weinheim, Germany, 2003. (e) Joule, J. A.; Mills, K.
Heterocyclic Chemistry at a Glance; Blackwell: Oxford, UK, 2007.
(5) (a) Krasovskiy, A.; Knochel, P. Angew. Chem. 2004, 116, 3396–
3399; Angew. Chem., Int. Ed. 2004, 43, 3333-3336. (b) Ren, H.;
Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215–4217. (c) Kopp, F.;
Krasovskiy, A.; Knochel, P. Chem. Commun. 2004, 2288–2289. (d) Ren,
H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543–545. (e) Liu,
C.-Y.; Knochel, P. Org. Lett. 2005, 7, 2543–2546. (f) Kopp, F.; Sklute, G.;
Polborn, K.; Marek, I.; Knochel, P. Org. Lett. 2005, 7, 3789–3791. (g) Liu,
C.-Y.; Ren, H.; Knochel, P. Org. Lett. 2006, 8, 617–619. (h) Kopp, F.;
Wunderlich, S.; Knochel, P. Chem. Commun. 2007, 2075–2077.
(1) (a) Handbook of Grignard Reagents; Silverman, G. S., Rakita, P. E.,
Eds.; Marcel Dekker: New York, 1996. (b) Grignard Reagents: New
DeVelopments; Richey, H. G., Jr., Ed.; Wiley: Chichester, UK, 2000. (c)
Main Group Metals in Organic Synthesis; Yamamoto, H., Oshima, K., Eds.;
Wiley-VCH: Weinheim, Germany, 2004. (d) Handbook of Functionalized
Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim, Germany, 2005
.
(2) (a) Rottla¨nder, M.; Boymond, L.; Be´rillon, L.; Lepreˆtre, A.; Varchi,
G.; Avolio, S.; Laaziri, H.; Que´guiner, G.; Ricci, A.; Cahiez, G.; Knochel,
P. Chem.sEur. J. 2000, 6, 767–770. (b) Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu,
V. A. Angew. Chem. 2003, 115, 4438–4456; Angew. Chem., Int. Ed. 2003,
42, 4302-4320. (c) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.;
Vu, V. A.; Knochel, P. Synthesis 2002, 565–569. (d) Ila, H.; Baron, O.;
Wagner, A. J.; Knochel, P. Chem. Lett. 2006, 35, 2–7. (e) Ila, H.; Baron,
O.; Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 583–593
.
(6) (a) Shi, L.; Chu, Y.; Knochel, P.; Mayr, H. Angew. Chem. 2008,
120, 208–210; Angew. Chem., Int. Ed. 2008, 47, 202-204. (b) Shi, L.;
Chu, Y.; Knochel, P.; Mayr, H. J. Org. Chem. 2009, 74, 2760–2764.
(3) Ro¨mpp Encyclopedia Natural Products; Steglich, W., Fugmann, B.,
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, Germany, 2000.
10.1021/ol9013393 CCC: $40.75
Published on Web 07/14/2009
 2009 American Chemical Society

different bromoheteroarenes with a substoichiometric amount
of i-PrMgCl·LiCl (typically 0.33 to 0.5 equiv) in THF at 0
°C. The resulting mixtures of aryl-magnesium reagents were
then quenched either with iodine or with methanol to give
the iodoarenes P1′/P2′ or the debrominated arenes P1/P2,
respectively (Scheme 1).
Scheme 1. Determination of Relative Br-Mg Exchange Rates
As in previous work,6a the product ratio was found to be
independent of the reaction time in most cases, indicating
kinetic reaction control. Exceptions will be discussed below.
The relative reactivities of R1 and R2 toward i-PrMgCl·LiCl
can be calculated by eq 1,7 which considers the change of
the ratio [R1]/[R2] during the course of the reaction.
k1
k2
(
[
] [
]
)
)
log R1 0/ R1 t
κ )
)
(1)
(
[
] [
]
log R2 0/ R2 t
With [R1]0 ) [R1]t + [P1]t and [R2]0 ) [R2]t + [P2]t,
eq 1 can be rewritten as:
log(1 + [P1]t/[R1]t)
log(1 + [P2]t/[R2]t)
κ )
(2)
For the calculation of κ by eq 2, the ratios [P1]t/[R1]t and
[P2]t/[R2]t were determined by GC analysis, as described
in the Supporting Information.
Each of the 13 heteroaryl bromides listed in Figure 1
was subjected to competition experiments with several
bromoarenes, to give the 24 competition constants κ
summarized in Figure 1, from which the krel values listed
in the left column of Figure 1 were obtained by a least-
squares optimization as described previously.8 Though the
reproducibility of the competition constants was worse
than in the case of the substituted bromobenzenes, the fair
agreement between the experimental values of κ and those
Figure 1. Relative reactivities of bromoarenes toward i-PrMgCl·
LiCl in THF at 0 °C and τ1/2 for 1 M solutions (bromobenzene: krel
1.0). Footnotes: (a) See ref 8. (b) krel not statistically corrected.
)
(7) Huisgen, R. Angew. Chem. 1970, 82, 783–794; Angew. Chem., Int.
Ed. 1970, 9, 751-762.
Org. Lett., Vol. 11, No. 15, 2009
3503

calculated from the averaged krel values shows the internal
consistency of the data.
2-Bromothiazole is so reactive that the corresponding
competition constant κ depended on the rate of mixing;
therefore, it was not employed for the calculation of krel by
the least-squares optimization.
Attempts to determine the relative reactivity of 2-bro-
mopyridine by comparison with 4-chlorobromobenzene
showed that the product ratio was strongly dependent on the
reaction time. While at short reaction times 4-chlorophenyl-
magnesium halide was the major component, at longer
reaction times, 2-pyridylmagnesium halide was the major
product. The reason for this dependence is not clear, because
independently synthesized 4-chlorophenylmagnesium halide
did not react with 2-bromopyridine under the reaction
conditions. Possibly, coordination of arylmagnesium halide
to the pyridine-nitrogen activates 2-bromopyridine; as a result
the exchange rate of 2-bromopyridine might increase with
the degree of conversion.
In previous work,6b second-order rate constants for the
reactions of two differently substituted bromobenzenes have
been determined, and it was reported that multiplication with
6.0 × 10-6 M-1 s-1 converts the krel values (with krel ) 1.0
for bromobenzene) into absolute second-order rate constants.
With the relationship τ1/2 ) 1/kc0 (k ) second-order rate
constant, c0 ) initial concentration), we have calculated the
half-reaction times listed in Figure 1 for the bromine-magne-
sium exchange in THF solutions which are 1 M in bro-
moarene and 1 M in i-PrMgCl·LiCl.
To determine the effect of LiCl on the exchange rates
quantitatively, we have studied the kinetics of the reaction
of 3-bromobenzo[b]thiophene with i-PrMgCl in the absence
of LiCl. From k2 ) 1.78 × 10-4 M-1 s-1 one can derive
that the reaction with i-PrMgCl is approximately 19 times
slower than that with i-PrMgCl·LiCl, and the half-reaction
time of a solution that is 1 M in i-PrMgCl and 3-bromoben-
zo[b]thiophene is 1.5 h. While in this case the use of LiCl-
activated i-PrMgCl is still favorable for achieving complete
conversion (>98%) within 4 h, the LiCl additive does not
appear to be necessary for the magnesiation of the upper
four compounds of Figure 1.
Figure 2. Relative reactivities of bromoheteroarenes toward
i-PrMgCl·LiCl (0 °C, THF).
mobenzo[b]thiophene corresponds to the previously reported
annelation effect in the benzene series (1-bromonaphthalene
is 5.5 times more reactive than bromobenzene).6b
While 2-bromothiophene, 2-bromofuran, and 2-bromopy-
rrole are more reactive than the corresponding 3-isomers,
2-bromopyridine is considerably less reactive than the 3- and
4-bromopyridines. The reactivity order 2-bromopyridine ,
3-bromopyridine < 4-bromopyridine reflects the equilibrium
mixture of deprotonated pyridines in the gas phase, which
contains 70-80% of 4-deprotonated, 20-30% of 3-depro-
tonated, and 0% of 2-deprotonated pyridine.10a As discussed
previously, repulsion between lone pairs may account for
this finding.10
As shown in Figures 1 and 2, 2-bromothiazole is by far
the most reactive bromoarene investigated in this study. With
an estimated half-reaction time of approximately 10-2 s it
becomes clear why the reactivity of this compound deter-
mined by competition experiments is not well reproducible
and the competition constant κ depends on the rate of
mixing.9
Figure 2 illustrates that the 2-bromo-substituted five-
membered heteroarenes, thiophene, furan, and pyrrole, are
considerably more reactive than the corresponding 3-bromo
derivatives. While 3-bromofuran and 3-bromothiophene react
almost 102 times faster than bromobenzene, 3-bromo-N-
methylpyrrole is even slightly less reactive than bromoben-
zene. Among the considerably more reactive 2-bromo-
substituted derivatives, 2-bromothiophene sticks out with a
krel value of more than 105 compared to bromobenzene. The
9-fold reactivity increase from 3-bromothiophene to 3-bro-
2,6-Dibromopyridine as well as the other dibromo-
substituted heteroarenes react much faster than the mono-
brominated derivatives, in line with the previously reported
accelerating inductive effect of halogens in bromobenzenes.6
3504
Org. Lett., Vol. 11, No. 15, 2009

The relative reactivities shown in Figure 2 can be used to
predict the regioselectivities of the bromine-magnesium
exchange in multiply brominated substrates. Thus, Que´guin-
er’s report that 2,3- and 2,5-dibromopyridines react selec-
tively in the 3- and 5-position, respectively (Scheme 2),11 is
However, because of subsequent isomerizations of lithiated
halogenopyridines, the site of the initial bromine-lithium
exchange is often not clear in these systems.12
In conclusion, competition experiments allowed us to
derive the relative reactivities of heteroaryl bromides toward
i-PrMgCl·LiCl in THF at 0 °C. It is found that most
heteroarenes undergo the bromine-magnesium exchange
reaction considerably faster than bromobenzene. While in
the series of the five-membered heteroarenes furan, pyrrole,
and thiophene, the 2-bromo derivatives are considerably more
reactive than the 3-substituted isomers, the relative reactivi-
ties are opposite in the pyridine series, and 2-bromopyridine
is much less reactive than 3- and 4-bromopyridine. Com-
parison with literature data on the reactivities of various
dibromopyridines showed that the regioselectivities of the
Br-Mg exchange in dibromopyridines can be predicted on
the basis of the krel values listed in Figure 1. The most
reactive compounds of this series, 3,4-dibromofuran, 2-bro-
mothiophene, 3,5-dibromopyridine, and 2-bromothiazole, are
so reactive that the 19 times less active i-PrMgCl (without
LiCl) appears to be appropriate for the Br-Mg exchange
reaction.
Scheme 2. Regioselective Grignard Reactions of
Dibromopyridines As Described by Que´guiner in Ref 11
in line with the 102 times higher krel value of 3-bromopyridine
compared to 2-bromopyridine.
Acknowledgment. Dedicated to Professor Manfred
Heuschmann on the occasion of his 60th birthday. We thank
the Alexander von Humboldt Foundation (research fellow-
ship to L.S.), the Deutsche Forschungsgemeinschaft (SFB
749), and the Fonds der Chemischen Industrie for support
of this work and Professor Manfred Schlosser for valuable
comments.
Furthermore, the product ratio reported for the function-
alization of 3,4-dibromopyridine (eq 3)11 is in agreement with
the similarity of the krel values of 3-bromopyridine and
4-bromopyridine, though the krel values of Figure 1 as well
as the relative gas phase acidities of these two positions10a
suggest a slightly preferred exchange of the 4-bromine atom.
Supporting Information Available: Experimental pro-
cedure and data for the determination of the relative exchange
rates κ and determination of absolute rate constants. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9013393
Analogous regioselectivities hold for the bromine-lithium
exchange, as shown by the selective lithiation of 2,5-
dibromopyridine in the 5-position by n-butyllithium.10
(9) (a) Rys, P. Acc. Chem. Res. 1976, 9, 345–351. (b) Yoshida, J.-i.,
Flash Chemistry; Wiley: Chichester, UK, 2008. (c) Yoshida, J.-i.; Nagaki,
A.; Yamada, T. Chem.sEur. J. 2008, 14, 7450–7459.
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1651. (b) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42, 257–
260.
(8) To obtain a consistent set of relative reactivities, the competition
constants obtained in this work and the 58 competition constants reported
previously have jointly been subjected to the least-squares minimization
described in ref 6b. In this way, the seemingly separate blocks of krel in
Figure 1 were tightly linked with each other. The consistency of competition
constants derived by quenching with methanol or iodine proves that the
method of quenching does not affect the results.
(11) (a) Tre´court, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
Que´guiner, G. Tetrahedron Lett. 1999, 40, 4339–4342. (b) Tre´court, F.;
Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Que´guiner, G. Tetrahedron
2000, 56, 1349–1360.
(12) (a) Mallet, M.; Que´guiner, G. Tetrahedron 1985, 41, 3433–3440.
(b) Mallet, M.; Que´guiner, G. Tetrahedron 1986, 42, 2253–2262.
Org. Lett., Vol. 11, No. 15, 2009
3505